Quantitative detection method of acryloyl chloride in ibrutinib bulk drug preparation process

A quantitative detection method and preparation process technology, which is applied in the field of quantitative detection of acryloyl chloride in the preparation process of ibrutinib bulk drug, can solve problems such as equipment damage and strong neurotoxicity, and achieve small instrument damage, strong specificity, and sensitivity high effect

Active Publication Date: 2021-03-26
河北合佳医药科技集团股份有限公司
View PDF5 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the detection methods for acryloyl chloride include the document "Gas Chromatographic Analysis of Acryloyl Chloride" ("Analytical Chemistry" 1999 No. 12, 1475) and the detection method for acryloyl chloride content disclosed in the invention patent CN109060978A. Aniline is derivatized and detected. Although this method solves the corrosion of the instrument by acryloyl chloride, the hydrogen chloride generated by the reaction will still cause damage to the equipment, and the aniline used in this method is a highly toxic substance that is very toxic to blood and nerves.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Quantitative detection method of acryloyl chloride in ibrutinib bulk drug preparation process
  • Quantitative detection method of acryloyl chloride in ibrutinib bulk drug preparation process
  • Quantitative detection method of acryloyl chloride in ibrutinib bulk drug preparation process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] 1. Sample testing

[0079] Preparation of the test solution: Accurately measure 5mL of the reaction solution in the preparation process of the ibrutinib API with batch number 20201104, put it in a 10mL volumetric flask, add 0.1mL of the internal standard solution, and then use methanol, N,N-di The volume ratio of methylformamide and triethylamine is a mixed solvent of 98.5:0.5:1, dissolve and dilute to the mark, shake well, and set aside.

[0080] 2 parallel samples of the reference solution, 3 injections for the first sample, 2 injections for the second sample; 2 parallel samples for the test solution, 2 injections for the first sample, 2 injections for the second sample . Inject headspace and record chromatograms. The results showed that acryloyl chloride was not detected.

[0081] 2. Methodological verification

[0082] System suitability test: blank solvent, reference substance solution and test solution, inject 1 needle each, record the chromatogram, see Figu...

Embodiment 2

[0090] Preparation of the test solution: Accurately measure 5mL of the reaction solution in the preparation process of the ibrutinib bulk drug with batch number 20201103, put it in a 100mL volumetric flask, add 0.1mL of the internal standard solution, and then use methanol, N,N-di The volume ratio of methylformamide and triethylamine is a mixed solvent of 98.5:0.5:1, dissolve and dilute to the mark, shake well, and set aside.

[0091] 2 parallel samples of the reference solution, 3 injections for the first sample, 2 injections for the second sample; 2 parallel samples for the test solution, 2 injections for the first sample, 2 injections for the second sample . Headspace sampling, recording chromatograms, see Figure 4 . The results showed that the detected amount of acryloyl chloride was 0.58ppm.

Embodiment 3

[0093] Preparation of the test solution: Accurately weigh 0.5g of the crude ibrutinib crude drug with batch number 20201104, put it in a 10mL volumetric flask, add 0.1mL of the internal standard solution, and then use methanol, N,N-dimethylformamide, The volume ratio of triethylamine is a mixed solvent of 98.5:0.5:1, dissolve and dilute to the mark, shake well, and set aside.

[0094] 2 parallel samples of the reference solution, 3 injections for the first sample, 2 injections for the second sample; 2 parallel samples for the test solution, 2 injections for the first sample, 2 injections for the second sample . Headspace sampling, recording chromatograms, see Figure 5 .The results showed that acryloyl chloride was not detected.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Column lengthaaaaaaaaaa
The inside diameter ofaaaaaaaaaa
Login to view more

Abstract

The invention discloses a method for quantitatively detecting acryloyl chloride in the ibrutinib bulk drug preparation process, and the method comprises the following steps: 1, preparing an internal standard solution; 2, preparing a reference substance stock solution; 3, preparing a reference substance solution; 4, preparing a test solution; 5, transferring 5.0 mL of the reference substance solution and 5.0 mL of the test solution into a headspace bottle, introducing a sample, and recording a chromatogram; 6, calculating the residual quantity of acryloyl chloride in the test sample by an internal standard method. Aiming at the defects in the prior art, the invention provides the headspace sample injection gas chromatography detection method which is low in toxicity, simple to operate, strong in specificity and high in accuracy and sensitivity, and is suitable for quantitative detection of acryloyl chloride in ibrutinib bulk drugs.

Description

technical field [0001] The invention belongs to the technical field of medical analysis, and in particular relates to a quantitative detection method for acryloyl chloride in the preparation process of ibrutinib bulk drug. Background technique [0002] Ibrutinib, known as Ibrutinib in English, is the world's first oral Bruton's tyrosine kinase inhibitor. It plays an anticancer role by inhibiting BTK required for tumor cell replication and metastasis, and has broad application prospects. [0003] The final step in the synthesis of ibrutinib bulk drug is the acyl chloride reaction between its intermediate N-1 and acryloyl chloride. Experiments have found that the excessive addition of acryloyl chloride is to produce ibrutinib impurity PCI-7581, namely (R)-1-3-(4-amino-3-(-4phenoxyphenyl)-1H-pyrazolo[ 3,4-d]pyrimidin-1-yl]piperidin-1-yl)-ethanone, with known impurity PCI-45228 namely (R)-1-(3-(4-phenoxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-chloropropyl-1-one is an impo...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): G01N30/88
CPCG01N30/88G01N2030/884
Inventor 刘振强刘东娜石畅畅刘艳君刘新元
Owner 河北合佳医药科技集团股份有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap